U.S. patent number 6,406,716 [Application Number 09/780,858] was granted by the patent office on 2002-06-18 for anticonvulsant containing composition for treating neuropathic pain.
This patent grant is currently assigned to Endo Pharmaceuticals Inc.. Invention is credited to Frank S. Caruso, John W. Lyle, Fredrick L. Minn.
United States Patent |
6,406,716 |
Caruso , et al. |
June 18, 2002 |
**Please see images for:
( Certificate of Correction ) ** |
Anticonvulsant containing composition for treating neuropathic
pain
Abstract
The effectiveness of an anticonvulsant such as gabapentin for
alleviating neuropathic pain is potentiated by a nontoxic
antagonist for the N-methyl-D-aspartate receptor or nontoxic
substance that blocks a major intracellular consequence of
N-methyl-D-aspartate receptor activation.
Inventors: |
Caruso; Frank S. (Colts Neck,
NJ), Minn; Fredrick L. (Blue Bell, PA), Lyle; John W.
(Belmar, NJ) |
Assignee: |
Endo Pharmaceuticals Inc.
(Chadds Ford, PA)
|
Family
ID: |
21820954 |
Appl.
No.: |
09/780,858 |
Filed: |
February 9, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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253598 |
Feb 22, 1999 |
6187338 |
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PCTUS9714680 |
Aug 21, 1997 |
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Current U.S.
Class: |
424/468; 424/455;
424/457; 424/464 |
Current CPC
Class: |
A61P
29/00 (20180101); A61P 25/02 (20180101); A61K
45/06 (20130101) |
Current International
Class: |
A61K
45/06 (20060101); A61K 45/00 (20060101); A61K
009/22 (); A61K 009/52 () |
Field of
Search: |
;424/457,468,489,455,464,423,451,456 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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0459695 |
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Dec 1991 |
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EP |
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0615749 |
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Aug 1994 |
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EP |
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8701036 |
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Feb 1987 |
|
WO |
|
8905641 |
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Jun 1989 |
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WO |
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8905642 |
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Jun 1989 |
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WO |
|
Other References
International Search Report for PCT/US 97/14680; International
filing date Aug. 21, 1997..
|
Primary Examiner: Spear; James M.
Attorney, Agent or Firm: Dilworth & Barese, LLP
Parent Case Text
This is a continuation of application Ser. No. 09/253,598 filed
Feb. 22, 1999 now U.S. Pat. No. 6,187,338, which is a continuation
of application Ser. No. PCT/US97/14680 filed Aug. 21, 1997. This
application claims benefit under 35 U.S.C. .sctn.119(e) of U.S.
Provisional Application No. 60/024,508 filed Aug. 23, 1996.
Claims
What is claimed is:
1. A neuropathic pain-alleviating composition for administration to
a mammal exhibiting, or about to exhibit, neuropathic pain which
comprises (a) gabapentin and (b) at least one nontoxic antagonist
for the N-methyl-D-aspartate receptor or nontoxic substance that
blocks a major intracellular consequence of N-methyl-D-aspartate
receptor activation, the combined amount of (a) and (b) in the
composition being a neuropathic pain-alleviating amount and the
amount of (b) in the composition being sufficient to potentiate the
neuropathic pain-alleviating effectiveness of (a).
2. The composition of claim 1 wherein (b) is at least one member
selected from the group consisting of dextromethorphan,
dextrorphan, amantadine, memantine and pharmaceutically acceptable
salt thereof.
3. The composition of claim 1 wherein (a) and (b) each is present
in a sustained release carrier.
4. A neuropathic pain-alleviating composition for administration to
a mammal exhibiting, or about to exhibit, neuropathic pain which
comprises (a) at least one member selected from the group
consisting of lamotrigine, gabapentin, valproic acid, topiramate,
famotodine, phenobarbital, diphenylhydantoin, phenytoin,
mephenytoin, ethotoin, mephobarbital, primidone, carbamazepine,
ethosuximide, methsuximide, phensuximide, trimethadione,
benzodiazepine, phenacemide, acetazolamide, progabide, clonazepam,
divalproex sodium, magnesium sulfate injection, metharbital,
paramethadione, phenytoin sodium, valproate sodium, clobazam,
sulthiame, dilantin, diphenylan and L-5-hydroxytryptophan, (b) at
least one nontoxic antagonist for the N-methyl-D-aspartate receptor
or nontoxic substance that blocks a major intracellular consequence
of N-methyl-D-aspartate receptor activation and (c) at least one
analgesic, the combined amount of (a) and (b) in the composition
being a neuropathic pain-alleviating amount and the amount of (b)
in the composition being sufficient to potentiate the neuropathic
pain-alleviating effectiveness of (a).
5. The composition of claim 4 wherein (b) is at least one member
selected from the group consisting of dextromethorphan,
dextrorphan, amantadine, memantine and pharmaceutically acceptable
salt thereof.
6. The composition of claim 5 wherein analgesic (c) is a
non-narcotic analgesic.
7. The composition of claim 6 wherein non-narcotic analgesic (c) is
at least one member selected from the group consisting of
acetaminophen and nonsteroidal anti-inflammatory drug.
8. The composition of claim 7 wherein the nonsteroidal
anti-inflammatory drug is at least one member selected from the
group consisting of aspirin, diclofenac, diflusinal, etodolac,
fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen,
indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic
acid, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxican,
sulindac, tolmetin and zomepirac.
9. A method of alleviating neuropathic pain in a mammal exhibiting,
or about to exhibit, neuropathic pain which comprises administering
to the mammal a neuropathic pain-alleviating composition which
comprises (a) gabapentin and (b) at least one nontoxic antagonist
for the N-methyl-D-aspartate receptor or nontoxic substance that
blocks a major intracellular consequence of N-methyl-D-aspartate
receptor activation, the combined amount of (a) and (b) in the
composition being a neuropathic pain-alleviating amount and the
amount of (b) in the composition being sufficient to potentiate the
neuropathic pain-alleviating effectiveness of (a).
10. The method of claim 9 wherein (b) is at least one member
selected from the group consisting of dextromethorphan,
dextrorphan, amantadine, memantine and pharmaceutically acceptable
salt thereof.
11. The method of claim 9 wherein (a) and (b) each is present in a
sustained release carrier.
12. A method of alleviating neuropathic pain in a mammal
exhibiting, or about to exhibit, neuropathic pain which comprises
administering to the mammal a neuropathic pain-alleviating
composition which comprises (a) at least one member selected from
the group consisting of lamotrigine, gabapentin, valproic acid,
topiramate, famotodine, phenobarbital, diphenylhydantoin,
phenytoin, mephenytoin, ethotoin, mephobarbital, primidone,
carbamazepine, ethosuximide, methsuximide, phensuximide,
trimethadione, benzodiazepine, phenacemide, acetazolamide,
progabide, clonazepam, divalproex sodium, magnesium sulfate
injection, metharbital, paramethadione, phenytoin sodium, valproate
sodium, clobazam, sulthiame, dilantin, diphenylan and
L-5-hydroxytryptophan, (b) at least one nontoxic antagonist for the
N-methyl-D-aspartate receptor or nontoxic substance that blocks a
major intracellular consequence of N-methyl-D-aspartate receptor
activation and (c) at least one analgesic, the combined amount of
(a) and (b) in the composition being a neuropathic pain-alleviating
amount and the amount of (b) in the composition being sufficient to
potentiate the neuropathic pain-alleviating effectiveness of
(a).
13. The method of claim 12 wherein (b) is at least one member
selected from the group consisting of dextromethorphan,
dextrorphan, amantadine, memantine and pharmaceutically acceptable
salt thereof.
14. The method of claim 12 wherein analgesic (c) is a non-narcotic
analgesic.
15. The method of claim 14 wherein non-narcotic analgesic (c) is at
least one member selected from the group consisting of
acetaminophen and nonsteroidal anti-inflammatory drug.
16. The method of claim 15 wherein the nonsteroidal
anti-inflammatory drug is at least one member selected from the
group consisting of aspirin, diclofenac, diflusinal, etodolac,
fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen,
indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic
acid, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxican,
sulindac, tolmetin and zomepirac.
17. A method of alleviating neuropathic pain in a mammal
exhibiting, or about to exhibit, neuropathic pain caused by
accidental trauma which comprises administering to the mammal a
neuropathic pain-alleviating composition which comprises (a)
gabapentin and (b) at least one nontoxic antagonist for the
N-methyl-D-aspartate receptor or nontoxic substance that blocks a
major intracellular consequence of N-methyl-D-aspartate receptor
activation, the combined amount of (a) and (b) in the composition
being a neuropathic pain-alleviating amount and the amount of (b)
in the composition being sufficient to potentiate the neuropathic
pain-alleviating effectiveness of (a).
18. The method of claim 17 wherein (b) is at least one member
selected from the group consisting of dextromethorphan,
dextrorphan, amantadine, memantine and pharmaceutically acceptable
salt thereof.
19. A method of alleviating neuropathic pain in a mammal
exhibiting, or about to exhibit, neuropathic pain caused by
accidental trauma which comprises administering to the mammal a
neuropathic pain-alleviating composition which comprises (a) at
least one member selected from the group consisting of lamotrigine,
gabapentin, valproic acid, topiramate, famotodine, phenobarbital,
diphenylhydantoin, phenytoin, mephenytoin, ethotoin, mephobarbital,
primidone, carbamazepine, ethosuximide, methsuximide, phensuximide,
trimethadione, benzodiazepine, phenacemide, acetazolamide,
progabide, clonazepam, divalproex sodium, magnesium sulfate
injection, metharbital, paramethadione, phenytoin sodium, valproate
sodium, clobazam, sulthiame, dilantin, diphenylan and
L-5-hydroxytryptophan, (b) at least one nontoxic antagonist for the
N-methyl-D-aspartate receptor or nontoxic substance that blocks a
major intracellular consequence of N-methyl-D-aspartate receptor
activation and (c) at least one analgesic, the combined amount of
(a) and (b) in the composition being a neuropathic pain-alleviating
amount and the amount of (b) in the composition being sufficient to
potentiate the neuropathic pain-alleviating effectiveness of
(a).
20. The method of claim 19 wherein (b) is at least one member
selected from the group consisting of dextromethorphan,
dextrorphan, amantadine, memantine and pharmaceutically acceptable
salt thereof.
21. The method of claim 20 wherein analgesic (c) is a non-narcotic
analgesic.
22. The method of claim 21 wherein non-narcotic analgesic (c) is at
least one member selected from the group consisting of
acetaminophen and nonsteroidal anti-inflammatory drug.
23. A method of alleviating neuropathic pain in a mammal
exhibiting, or about to exhibit, neuropathic pain caused by a tumor
which comprises administering to the mammal a neuropathic
pain-alleviating composition which comprises (a) gabapentin and (b)
at least one nontoxic antagonist for the N-methyl-D-aspartate
receptor or nontoxic substance that blocks a major intracellular
consequence of N-methyl-D-aspartate receptor activation, the
combined amount of (a) and (b) in the composition being a
neuropathic pain-alleviating amount and the amount of (b) in the
composition being sufficient to potentiate the neuropathic
pain-alleviating effectiveness of (a).
24. The method of claim 23 wherein (b) is at least one member
selected from the group consisting of dextromethorphan,
dextrorphan, amantadine, memantine and pharmaceutically acceptable
salt thereof.
25. A method of alleviating neuropathic pain in a mammal
exhibiting, or about to exhibit, neuropathic pain caused by a tumor
which comprises administering to the mammal a neuropathic
pain-alleviating composition which comprises (a) at least one
member selected from the group consisting of lamotrigine,
gabapentin, valproic acid, topiramate, famotodine, phenobarbital,
diphenylhydantoin, phenytoin, mephenytoin, ethotoin, mephobarbital,
primidone, carbamazepine, ethosuximide, methsuximide, phensuximide,
trimethadione, benzodiazepine, phenacemide, acetazolamide,
progabide, clonazepam, divalproex sodium, magnesium sulfate
injection, metharbital, paramethadione, phenytoin sodium, valproate
sodium, clobazam, sulthiame, dilantin, diphenylan and
L-5-hydroxytryptophan, (b) at least one nontoxic antagonist for the
N-methyl-D-aspartate receptor or nontoxic substance that blocks a
major intracellular consequence of N-methyl-D-aspartate receptor
activation and (c) at least one analgesic, the combined amount of
(a) and (b) in the composition being a neuropathic pain-alleviating
amount and the amount of (b) in the composition being sufficient to
potentiate the neuropathic pain-alleviating effectiveness of
(a).
26. The method of claim 23 wherein (b) is at least one member
selected from the group consisting of dextromethorphan,
dextrorphan, amantadine, memantine and pharmaceutically acceptable
salt thereof.
27. The method of claim 26 wherein analgesic (c) is a non-narcotic
analgesic.
28. The method of claim 27 wherein non-narcotic analgesic (c) is at
least one member selected from the group consisting of
acetaminophen and nonsteroidal anti-inflammatory drug.
29. A method of alleviating neuropathic pain in a mammal
exhibiting, or about to exhibit, neuropathic pain caused by
cervical spine disease which comprises administering to the mammal
a neuropathic pain-alleviating composition which comprises (a)
gabapentin and (b) at least one nontoxic antagonist for the
N-methyl-D-aspartate receptor or nontoxic substance that blocks a
major intracellular consequence of N-methyl-D-aspartate receptor
activation, the combined amount of (a) and (b) in the composition
being a neuropathic pain-alleviating amount and the amount of (b)
in the composition being sufficient to potentiate the neuropathic
pain-alleviating effectiveness of (a).
30. The method of claim 29 wherein (b) is at least one member
selected from the group consisting of dextromethorphan,
dextrorphan, amantadine, memantine and pharmaceutically acceptable
salt thereof.
31. A method of alleviating neuropathic pain in a mammal
exhibiting, or about to exhibit, neuropathic pain caused by
cervical spine disease which comprises administering to the mammal
a neuropathic pain-alleviating composition which comprises (a) at
least one member selected from the group consisting of lamotrigine,
gabapentin, valproic acid, topiramate, famotodine, phenobarbital,
diphenylhydantoin, phenytoin, mephenytoin, ethotoin, mephobarbital,
primidone, carbamazepine, ethosuximide, methsuximide, phensuximide,
trimethadione, benzodiazepine, phenacemide, acetazolamide,
progabide, clonazepam, divalproex sodium, magnesium sulfate
injection, metharbital, paramethadione, phenytoin sodium, valproate
sodium, clobazam, sulthiame, dilantin, diphenylan and
L-5-hydroxytryptophan, (b) at least one nontoxic antagonist for the
N-methyl-D-aspartate receptor or nontoxic substance that blocks a
major intracellular consequence of N-methyl-D-aspartate receptor
activation and (c) at least one analgesic, the combined amount of
(a) and (b) in the composition being a neuropathic pain-alleviating
amount and the amount of (b) in the composition being sufficient to
potentiate the neuropathic pain-alleviating effectiveness of
(a).
32. The method of claim 31 wherein (b) is at least one member
selected from the group consisting of dextromethorphan,
dextrorphan, amantadine, memantine and pharmaceutically acceptable
salt thereof.
33. The method of claim 32 wherein analgesic (c) is a non-narcotic
analgesic.
34. The method of claim 33 wherein non-narcotic analgesic (c) is at
least one member selected from the group consisting of
acetaminophen and nonsteroidal anti-inflammatory drug.
35. A method of alleviating neuropathic pain in a mammal
exhibiting, or about to exhibit, neuropathic pain caused by lumbar
spine disease which comprises administering to the mammal a
neuropathic pain-alleviating composition which comprises (a)
gabapentin and (b) at least one nontoxic antagonist for the
N-methyl-D-aspartate receptor or nontoxic substance that blocks a
major intracellular consequence of N-methyl-D-aspartate receptor
activation, the combined amount of (a) and (b) in the composition
being a neuropathic pain-alleviating amount and the amount of (b)
in the composition being sufficient to potentiate the neuropathic
pain-alleviating effectiveness of (a).
36. The method of claim 35 wherein (b) is at least one member
selected from the group consisting of dextromethorphan,
dextrorphan, amantadine, memantine and pharmaceutically acceptable
salt thereof.
37. A method of alleviating neuropathic pain in a mammal
exhibiting, or about to exhibit, neuropathic pain caused by lumbar
spine disease which comprises administering to the mammal a
neuropathic pain-alleviating composition which comprises (a) at
least one member selected from the group consisting of lamotrigine,
gabapentin, valproic acid, topiramate, famotodine, phenobarbital,
diphenylhydantoin, phenytoin, mephenytoin, ethotoin, mephobarbital,
primidone, carbamazepine, ethosuximide, methsuximide, phensuximide,
trimethadione, benzodiazepine, phenacemide, acetazolamide,
progabide, clonazepam, divalproex sodium, magnesium sulfate
injection, metharbital, paramethadione, phenytoin sodium, valproate
sodium, clobazam, sulthiame, dilantin, diphenylan and
L-5-hydroxytryptophan, (b) at least one nontoxic antagonist for the
N-methyl-D-aspartate receptor or nontoxic substance that blocks a
major intracellular consequence of N-methyl-D-aspartate receptor
activation and (c) at least one analgesic, the combined amount of
(a) and (b) in the composition being a neuropathic pain-alleviating
amount and the amount of (b) in the composition being sufficient to
potentiate the neuropathic pain-alleviating effectiveness of
(a).
38. The method of claim 37 wherein (b) is at least one member
selected from the group consisting of dextromethorphan,
dextrorphan, amantadine, memantine and pharmaceutically acceptable
salt thereof.
39. The method of claim 38 wherein analgesic (c) is a non-narcotic
analgesic.
40. The method of claim 39 wherein non-narcotic analgesic (c) is at
least one member selected from the group consisting of
acetaminophen and nonsteroidal anti-inflammatory drug.
41. A method of alleviating neuropathic pain in a mammal
exhibiting, or about to exhibit, neuropathic pain caused by painful
neuropathy which comprises administering to the mammal a
neuropathic pain-alleviating composition which comprises (a)
gabapentin and (b) at least one nontoxic antagonist for the
N-methyl-D-aspartate receptor or nontoxic substance that blocks a
major intracellular consequence of N-methyl-D-aspartate receptor
activation, the combined amount of (a) and (b) in the composition
being a neuropathic pain-alleviating amount and the amount of (b)
in the composition being sufficient to potentiate the neuropathic
pain-alleviating effectiveness of (a).
42. The method of claim 41 wherein (b) is at least one member
selected from the group consisting of dextromethorphan,
dextrorphan, amantadine, memantine and pharmaceutically acceptable
salt thereof.
43. A method of alleviating neuropathic pain in a mammal
exhibiting, or about to exhibit, neuropathic pain caused by a
painful neuropathy which comprises administering to the mammal a
neuropathic pain-alleviating composition which comprises (a) at
least one member selected from the group consisting of lamotrigine,
gabapentin, valproic acid, topiramate, famotodine, phenobarbital,
diphenylhydantoin, phenytoin, mephenytoin, ethotoin, mephobarbital,
primidone, carbamazepine, ethosuximide, methsuximide, phensuximide,
trimethadione, benzodiazepine, phenacemide, acetazolamide,
progabide, clonazepam, divalproex sodium, magnesium sulfate
injection, metharbital, paramethadione, phenytoin sodium, valproate
sodium, clobazam, sulthiame, dilantin, diphenylan and
L-5-hydroxytryptophan, (b) at least one nontoxic antagonist for the
N-methyl-D-aspartate receptor or nontoxic substance that blocks a
major intracellular consequence of N-methyl-D-aspartate receptor
activation and (c) at least one analgesic, the combined amount of
(a) and (b) in the composition being a neuropathic pain-alleviating
amount and the amount of (b) in the composition being sufficient to
potentiate the neuropathic pain-alleviating effectiveness of
(a).
44. The method of claim 43 wherein (b) is at least one member
selected from the group consisting of dextromethorphan,
dextrorphan, amantadine, memantine and pharmaceutically acceptable
salt thereof.
45. The method of claim 44 wherein analgesic (c) is a non-narcotic
analgesic.
46. The method of claim 45 wherein non-narcotic analgesic (c) is at
least one member selected from the group consisting of
acetaminophen and nonsteroidal anti-inflammatory drug.
Description
BACKGROUND OF THE INVENTION
This invention relates to a composition and method for alleviating
neuropathic pain. More particularly, this invention is directed to
a composition and method for alleviating neuropathic pain in which
a neuropathic pain-alleviating amount of an anticonvulsant is
combined with an anticonvulsant-potentiating amount of a nontoxic
antagonist, or blocker, for the N-methyl-D-aspartate (NMDA)
receptor or nontoxic substance that blocks a major intracellular
consequence of NMDA receptor activation.
Neuropathic pain is pain that is due to functional abnormalities of
the nervous system. Fields, "Pain", McGraw-Hill, Inc. (1987), pp.
133 et seq. There are a variety of possible mechanisms by which
nerve dysfunction can cause neuropathic pain: hyperactivity in
primary afferent or central nervous system (CNS) nociceptive
neurons, loss of central inhibitory connections, and increased
activity in sympathetic efferents. Neuropathic pain typically
occurs following injury to elements of the nervous system involved
in nociception, such as peripheral nerve injury, in which the
lesions deafferent the nociceptive pathway, the resultant pain
sometimes being referred to deafferentation pain. Neuropathic pain
is much more likely to occur with peripheral than with central
nervous system damage. Examples of causes of painful nerve injury
are: accidental trauma, tumors, cerval or lumbar spine disease, and
surgical procedures. These injuries usually involve one or two
peripheral nerves or nerve roots, and the pain is felt in the body
region normally innervated by the damaged nerves. Additionally,
there are also toxic, metabolic, and hereditary causes of painful
polyneuropathies, e.g., alcohol abuse, diabetes mellitus. These
tend to be symmetrical and are most severe on the distal limbs.
SUMMARY OF THE INVENTION
In accordance with the present invention, a drug composition is
provided which comprises a neuropathic pain-alleviating amount of
at least one anticonvulsant in combination with an
anticonvulsant-potentiating amount of at least one nontoxic
antagonist for the NMDA receptor or nontoxic substance that blocks
a major intracellular consequence of NMDA receptor activation.
Further in accordance with the present invention, a method of
alleviating neuropathic pain is provided which comprises
administering to a mammal exhibiting neuropathic pain (a) a
neuropathic pain-alleviating amount of at least one anticonvulsant
and (b) an anticonvulsant-potentiating amount of at least one
nontoxic antagonist for the NMDA receptor or nontoxic substance
that blocks a major intracellular consequence of NMDA receptor
activation with (a) being administered prior to, with or following
the administration of (b).
The expression "N-methyl-D-aspartate receptor" shall be understood
to include all of the binding site subcategories associated with
the NMDA receptor, e.g., the glycine-binding site, the
phenylcyclidine (PCP)-binding site, etc., as well as the NMDA
channel. Thus, the invention herein contemplates the use of
nontoxic substances that block an NMDA receptor binding site, e.g.,
dextrorphan, or the NMDA channel, e.g., a source of magnesium such
as magnesium sulfate.
The term "nontoxic" as used herein shall be understood in a
relative sense and is intended to designate any substance that has
been approved by the United States Food and Drug Administration
("FDA") for administration to humans or, in keeping with
established regulatory criteria and practice, is susceptible to
approval by the FDA for administration to humans. The term
"nontoxic" is also used herein to distinguish the NMDA receptor
antagonists, or blockers, that are useful in the practice of the
present invention from NMDA receptor antagonists such as MK 801
(the compound
5-methyl-10,11-dihydro-SH-dibenze[a,d]cyclohepten-5,10-imine), CPP
(the compound 3-[2-carboxypiperazin-4-yl]propyl-1-phosphonic acid)
and PCP (the compound 1-(1-phenylcyclohexyl)piperidine) whose
toxicities effectively preclude their therapeutic use.
The expression "neuropathic pain-alleviating" shall be understood
herein to include the expressions "neuropathic pain-suppressing"
and "neuropathic pain-inhibiting" as the invention is applicable to
the alleviation of existing neuropathic pain as well as the
suppression or inhibition of neuropathic pain which would otherwise
ensue from an imminent neuropathic pain-causing event.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Any of the pain-alleviating anticonvulsants can be used herein. For
extensive listings of anticonvulsants, see, e.g., Goodman and
Gilman's "The Pharmaceutical Basis Of Therapeutics", 8th ed.,
McGraw-Hill, Inc. (1990), pp. 436-462, and "Remington's
Pharmaceutical Sciences", 17th ed., Mack Publishing Company (1985),
pp. 1075-1083. Specific neuropathic pain-alleviating
anticonvulsants that can be used herein include lamotrigine,
gabapentin, valproic acid, topiramate, famotodine, phenobarbital,
diphenylhydantoin, phenytoin, mephenytoin, ethotoin, mephobarbital,
primidone, carbamazepine, ethosuximide, methsuximide, phensuximide,
trimethadione, benzodiazepine, phenacemide, acetazolamide,
progabide, clonazepam, divalproex sodium, magnesium sulfate
injection, metharbital, paramethadione, phenytoin sodium, valproate
sodium, clobazam, sulthiame, dilantin, diphenylan and
L-5-hydroxytryptophan.
Among the nontoxic substances that block the NMDA receptor and as
such are useful for potentiating the neuropathic pain-alleviating
activity of the anticonvulsant in accordance with this invention
are dextromethorphan ((+)-3-hydroxy-N-methylmorphinan), its
metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan),
amantadine (1-amino adamantine), memantine (3,5
dimethylaminoadamantone), their mixtures and their pharmaceutically
acceptable salts. Other useful nontoxic substances that block the
NMDA receptor include pyrroloquinoline quinone and
cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid.
In addition to, or in place of, a blocker for the NMDA receptor, at
least one nontoxic substance that blocks a major intracellular
consequence of NMDA receptor activation can also be used.
Activation of the NMDA receptor, a subtype of excitatory amino acid
receptors, induces a number of changes in the functional activity
of nerve cells and, in particular, their capacity for excitability
or inhibition in the presence of an addictive substance via an
increase in intracellular Ca++ concentration. The major
consequences of NMDA receptor activation include the following
sequences, or cascades, of events occurring within nerve cells:
a) translocation and activation of protein kinases such as protein
kinase C.fwdarw.phosphorylation of substrate proteins such as
cytosolic enzymes, channel proteins, receptor proteins,
etc..fwdarw.changes in functional activity;
b) initiation of early gene (c-fos, c-jun, zif-268, etc.)
expression by either increased intracellular Ca++ or Ca++-activated
protein kinases.fwdarw.expression of functional genes responsible
for production of cellular enzymes (such as protein kinases),
receptor proteins (such as the NMDA receptor), ion channel proteins
(such as K+, Na+, Ca++ channels), neuropeptides (such as
dynorphin), etc..fwdarw.changes in functional activity;
c) Ca++/calmodulin (or other Ca++ binding proteins) induced
activation of enzymes and other cellular
components.fwdarw.activation of Ca++/calmodulin-protein kinase
systems such as Ca++/calmodulin kinase
II.fwdarw.autophosphorylation of enzymes (e.g., Ca++/calmodulin
kinase II) or other functional proteins.fwdarw.changes in
functional activity;
d) Ca++/calmodulin induced activation of constitutive nitric oxide
synthase as well as induction of inducible nitric oxide
synthase.fwdarw.production of nitric oxide.fwdarw.i) production of
cyclic guanosine monophosphate via activation of guanosine cyclase
resulting in activation of protein kinases and early gene
expression; ii) direct protein modification such as enzymes,
receptor and/or channel proteins; iii) lipid membrane modification
and/or nucleic acid modification via scavenge of free radicals; iv)
induction of neurotoxicity at higher nitric oxide levels; v)
retrograde actions in adjacent neurons or glial cells such as
facilitation of glutamate release/NMDA receptor activation and/or
inhibition of post-synaptic NMDA receptors.fwdarw.changes in
functional activity;
e) interactions with the cyclic adenosine monophosphate/protein
kinase A system, the phospholipase C-inositol
triphosphate-Ca++/diacylglycerol-protein kinase system, the
phospholipase A2-arachidonic acid/prostanoids/leukotrienes
system.fwdarw.changes in functional activity induced by second
messenger systems other than NMDA
receptor/Ca++/Ca++-calmodulin/protein kinase systems; and,
f) interactions with other excitatory amino acid receptor subtypes
including non-NMDA receptors and metabotropic receptors as well as
intracellular events subsequent to the activation of these
excitatory amino acid receptor subtypes.fwdarw.changes in
functional activity induced by the non-NMDA and metabotropic
receptor activation.
A substance that blocks the NMDA receptor will effectively prevent
all of the foregoing major intracellular sequences of events from
taking place. However, even with activation of the NMDA receptor,
it is still possible to treat neuropathic pain in accordance with
this invention by administering the anticonvulsant and a nontoxic
substance that blocks at least one of the foregoing major
intracellular sequences of events brought about by activation of
the NMDA receptor. Thus, e.g., a substance that interferes with
translocation and activation of protein kinase C or with calmodulin
induced activation of constitutive nitric oxide synthase as well as
induction of inducible nitric oxide synthase is also useful for the
practice of this invention.
Nontoxic substances that block a major intracellular consequence of
NMDA receptor activation and are therefore useful in the practice
of the invention include inhibitors of protein kinase C, e.g.,
gangliosides such as ganglioside GM.sub.1 (monosialoganglioside)
and ganglioside GT.sub.1b (trisialoganglioside); amphipathic long
chain bases such as sphingosine, N,N,N-trimethylsphingosine,
sphinganine and psychosine; quinolyloxazole-2-ones such as
4-methyl-5-(3-quinolinyl)-2-(3H)-oxazolone and
phenyl-5-(2-quinolinyl)-2-3(3H)-oxazolone;
1,4-bis-(amino-hydroxyalkylamino)-anthraquinones such as
1,4-bis-(3-propylamino-2-hydroxypropylamino)-9,10anthracenedione
and
1,4-bis-(3-benzylamino-2-hydroxypropylamino)-9,10anthracenedione;
and, mixtures and pharmaceutically acceptable salts of any of the
foregoing.
Additional nontoxic substances that block a major intracellular
consequence of NMDA receptor activation and as such are useful in
the practice of the invention include inhibitors of calmodulin,
such as the phenothiazines, in particular, chlorpromazine,
chlorpromazine sulfoxide, prochlorperazine dimaleate, perphenazine,
trifluoperazine, fluphenazine, fluphenazine enanthate, fluphenazine
decanoate, thioridazine, mesoridazine besylate, piperacetazine,
acetophenazine dimaleate, carphenazine dimaleate, butaperazine
dimaleate and phenothiazine sulfoxide; naphthalenesulfonamides such
as N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide,
N-(6-aminohexyl)-5-chloro-2-naphthalenesulfonamide and
N-(6-aminohexyl)-5-bromo-2-naphthalenesulfonamide;
4-substituted-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepines such as
1,3-dihydro-1-{1-[(4-methyl-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepin-4-yl)met
hyl]-4-piperidinyl}-2H-benzimidazol-2-one; benzhydryls such as
N-[2](diphenylmethylthioethyl]-2-(trifluoromethyl)benzeneethanamine,
N-[2-(bis(4-fluorophenyl)
methylthio)ethyl]-2-(trifluoromethyl)benzeneethanamine and
N-[2-(bis(4-fluorophenyl)methylthio)ethyl]-3-(trifluoromethyl)benzeneethan
amine; tricyclic antidepressant drugs such as imipramine,
2-chloroimipramine and amitriptyline; penfluridol; haloperidol;
pimozide; clozapine; calmidazolin; and, mixtures and
pharmaceutically acceptable salts of any of the foregoing.
Of the two groups, the NMDA-receptor antagonists are preferred and
of these, dextromethorphan is especially preferred due to its wide
use in over-the-counter medications where it functions as a cough
suppressant.
With regard to dosage levels, the anticonvulsant must be present in
a neuropathic pain-alleviating amount, e.g., at a level
corresponding to the generally recommended adult human dosages for
a particular anticonvulsant, and the NMDA receptor blocker or
substance that blocks a major intracellular consequence of NMDA
activation must be present at a level that potentiates the
neuropathic pain-alleviating effectiveness of the anticonvulsant.
Specific dosage levels for the anticonvulsants that can be used
herein as given, inter alia, in the "Physicians' Desk Reference",
1996 Edition (Medical Economics Data Production Company, Montvale,
N.J.) as well as in other reference works including Goodman and
Gilman's "The Pharmaceutical Basis of Therapeutics" and
"Remington's Pharmaceutical Sciences" both of which as referred to
above. Given the wide variation in dosage level of the
anticonvulsant which depends to a large extent on the specific
anticonvulsant being administered, there can similarly be a wide
variation in the dosage level of the NMDA receptor blocker or
substance that blocks a major intracellular consequence of NMDA
receptor activation. These amounts can be determined for a
particular drug combination in accordance with this invention
employing routine experimental testing. In case of the
anticonvulsant phenobarbital and the NMDA receptor blocker
dextromethorphan, dosages of from 50 to 300 mg/day of the former
coadministered with from 30 to 120 mg/day of the latter will
usually provide acceptable results.
While the neuropathic pain-alleviating anticonvulsant and
anticonvulsant-potentiating nontoxic NMDA receptor blocker or
nontoxic substance that blocks a major intracellular consequence of
NMDA receptor activation need not be administered together, they
must both be present in the patient at effective levels at the same
time. While it is within the scope of the invention to separately
administer the anticonvulsant and the NMDA receptor blocker or
nontoxic substance that blocks a major intracellular consequence of
NMDA receptor activation, as a matter of convenience, it is
preferred that these drugs be coadministered in a single dosage
form. All modes of administrations are contemplated, e.g., orally,
rectally, parenterally, intranasally and topically.
A therapeutic composition containing the anticonvulsant and
nontoxic NMDA receptor blocker or nontoxic substance that blocks a
major intracellular consequence of NMDA receptor activation will
ordinarily be formulated with one or more pharmaceutically
acceptable ingredients in accordance with known and established
practice. Thus, the composition can be formulated as a liquid,
powder, elixir, injectable solution, etc. Formulations for oral use
can be provided as tablets or hard capsules wherein the
pharmacologically active ingredients are mixed with an inert solid
diluent such as calcium carbonate, calcium phosphate or kaolin, or
as soft gelatin capsules wherein the active ingredients are mixed
with an oleaginous medium, e.g., liquid paraffin or olive oil.
Aqueous suspensions can include pharmaceutically acceptable
excipients such as suspending agents,.e.g., sodium carboxymethyl
cellulose, methylcellulose, hydroxypropylmethylcellulose, sodium
alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;
dispersing or wetting agents such as naturally occurring
phosphatide, e.g., lecithin, or condensation, products of an
alkylene oxide with fatty acids, e.g., polyoxyethylene stearate, or
condensation products of ethylene oxide with long chain aliphatic
alcohols, e.g., heptadecaethylene-oxycetanol, or condensation
products of ethylene oxide with partial esters derived from fatty
acids and a hexitol, e.g., polyoxyethylene sorbitol monoleate or
condensation products of ethylene oxide with partial esters derived
from fatty acids and hexitol anhydrides, e.g., polyoxyethylene
sorbitan monoleate. The aqueous suspensions can also contain one or
more preservatives, e.g., ethyl-or-n-propyl-p-hydroxy benzoate, one
or more coloring agents, one or more flavoring agents and one or
more sweetening agents, such as sucrose, saccharin or sodium or
calcium cyclamate.
In addition to anticonvulsant and nontoxic NMDA receptor blocker or
nontoxic substance that blocks a manor intracellular consequence of
NMDA receptor activation, the therapeutic composition herein can
optionally contain at least one other pharmacologically active
substance e.g., a non-narcotic analgesic such as acetaminophen or a
non-steroidal anti-inflammatory drug (NSAID) such as aspirin,
diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal,
flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac,
meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin,
phenylbutazone, piroxicam, sulindac, tolmetin, zomepirac, and the
like.
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